Pharmaceutical dosage form and method for the production thereof

ABSTRACT

The invention relates to a method for producing a pharmaceutical dosage form as tablets, pellets and/or in the form of an active ingredient-containing matrix, whereby the tablets, pellets and/or active ingredient-containing matrix contain a pharmaceutical active ingredient and a copolymer serving as a coating agent and/or binding agent, and optionally contain a core and pharmaceutically common additives. According to the invention, the copolymer, the pharmaceutical active ingredient, the optionally present core and/or the pharmaceutically common additives are processed using known techniques by melting, injection molding, extrusion, wet granulation, casting, dipping, spreading out, spraying on, or pressing to form tablets, pellets and/or an active ingredient-containing matrix. The inventive method is characterized in that a copolymer is used that consists of 20 to 34 wt. % methacrylic acid, 20 to 69 wt. % methylacrylate and 0 to 40 wt. % ethylacrylate and, optionally, of 0 to 10 wt. % of additional vinylically copolymerizable monomers with the provision that the glass transition temperature of the copolymer is no higher than 60° C. according to ISO 11357-2, Item 3.3.3. The invention also relates to the pharmaceutical dosage form produced according to this method, said copolymer and the use thereof.

The invention relates to a process for producing drug forms, to the drugforms themselves, to the copolymer present therein, and to its use forproducing the drug form.

PRIOR ART

EP 0 704 208 A2 describes coating agents and binders for drug coveringssoluble in intestinal juice. These comprise copolymers of 10 to 25% byweight methacrylic acid, 40 to 70% by weight methyl acrylate and 20 to40% by weight methyl methacrylate. As well as monolayer coatings, thedescription mentions multilayer coating systems. These may be composedof a core, comprising for example a basic or a water-sensitive activeingredient, may have an insulating layer of another coating material,such as cellulose ethers, cellulose esters or a cationicpolymethacrylate of the EUDRAGIT® type, for example, including EUDRAGIT®RS and RL, and are then additionally provided with the above-mentionedcovering soluble in intestinal juice.

EP 0 704 207 A2 describes thermoplastic materials for drug coveringssoluble in intestinal juice. These comprise copolymers of 16 to 40% byweight acrylic or methacrylic acid, 30 to 80% by weight methyl acrylateand 0 to 40% by weight other alkyl esters of acrylic acid and/ormethacrylic acid. The minimum film-forming temperature (MFT according toDIN 53 778) is in the range between 0 and 25° C., so that processing ispossible at room temperature without adding plasticizer. The breakingelongation of the films, measured in accordance with DIN 53 455, isgenerally 50% or more at a maximum triethyl citrate content of 10% byweight.

PROBLEM AND SOLUTION

EP 0 704 207 A2 and EP 0 704 208 A2 describe copolymers for producingdrug forms based on (meth)acrylate monomers, which form comparativelyflexible films and have release profiles that are suitable for manydrugs in the range of high pH values above about 6.0.

The permanently ongoing development of drug forms is increasinglydemanding better and better coating agents and binders. Coating agentsand binders are being developed which, sometimes in conjunction withfurther additives, are allowing increasingly more specific releasecharacteristics, tailored to the respective active ingredient.

Another trend in development, however, is generally to minimize thefraction of additives as compared with the active ingredient itself. Inthe case of drug forms with a functional coating, therefore, the aim isto reduce the thickness of the coating. This has its limits, firstly inthe target release characteristics for the drug itself and secondly inthe mechanical stability of the coatings. With very thin coatings thereis always a risk of mechanical damage in the course of production orstorage.

Furthermore, even today many active ingredients are provided in the formof multiparticulate drug forms. As a result of the amount of particlespresent in a drug form, success is being achieved in limitingfluctuations in dosage caused by fluctuating thicknesses of thefunctional coatings. Since the production of multiparticulate drug formsis carried out by compressing coated pellets containing active substancetogether with auxiliaries under pressures which are in some cases high,many otherwise very suitable polymeric coating agents are notappropriate for this drug form, since they do not withstand themechanical loads with sufficient reliability or withstand them only whenthe coatings are applied with a disproportionate thickness.

EP 0 704 207 A2 and EP 0 704 208 A2 describe copolymers for producingdrug forms based on (meth)acrylate monomers, which form comparativelyflexible films and have release profiles that are suitable for manydrugs in the range of high pH values above about 6.0. As has been found,the copolymers described specifically by EP 0 704 207 A2 have poorresistance, at least to relatively high mechanical loads. The polymersdescribed in EP 0 704 208 A2, however, dissolve only above a pH of 6.5,and hence in relatively low sections of the intestine. They aretherefore unsuitable for active ingredients whose absorption takes placepreferably in the upper regions of the intestine.

The problem was seen as being to provide drug forms soluble inintestinal juice which do not release the active ingredient until a pHof about 5.8 to about 6.0 and which at the same time form mechanicallystable, nontacky films without disproportionate addition of plasticizer.In particular the intention was to provide formulations which satisfythe stringent mechanical requirements associated with the production ofmultiparticulate drug forms.

The problem is solved by a process for producing a drug form as atablet, as a drug forms comprising pellets and/or in the form of anactive ingredient matrix, the tablets, pellets and/or active ingredientmatrix comprising an active pharmaceutical ingredient and a copolymer ascoating agent and/or binder, and, if desired, a core andpharmaceutically customary excipients, by processing the copolymer, theactive pharmaceutical ingredient, the core if present and/or thepharmaceutically customary excipients in conventional manner by melting,injection molding, extrusion, wet granulation, casting, dipping,spreading, spraying or compression to form tablets, a drug formcomprising pellets and/or an active ingredient matrix,

characterized in that a copolymer is used which is composed of

-   -   20 to 34% by weight methacrylic acid,    -   20 to 69% by weight methyl acrylate and    -   0 to 40% by weight ethyl acrylate and, if desired,    -   0 to 10% by weight further vinylically copolymerizable monomers,        with the proviso that the glass transition temperature of the        copolymer in accordance with ISO 11357-2, section 3.3.3, is not        more than 60° C.

The invention further provides the drug form itself and also thecopolymer and its use for producing the drug form.

IMPLEMENTATION OF THE INVENTION

The invention relates to a process for producing a drug form in the formof a tablet, drug form comprising pellets and/or active ingredientmatrix, the tablets, pellets and/or active ingredient matrix comprisingan active pharmaceutical substance and a copolymer as coating agentand/or binder, and, if desired, a core and pharmaceutically customaryexcipients, by processing the copolymer, the active pharmaceuticalingredient, the core if present and/or the pharmaceutically customaryexcipients in conventional manner, by melting, injection molding,extrusion, wet granulation, casting, spreading, spraying or compressionto form tablets or pellets and/or an active ingredient matrix.

Copolymer

Key to the invention is the use of a copolymer which is composed of

-   -   20 to 34% by weight methacrylic acid and/or acrylic acid    -   20 to 69% by weight methyl acrylate and    -   0 to 40% by weight ethyl acrylate and/or, if desired,    -   0 to 10% by weight further vinylically copolymerizable monomers,        with the proviso that the glass transition temperature of the        copolymer in accordance with ISO 11357-2 (3.3.3, midpoint        temperature T_(mg)), is not more than 60° C.

The copolymer is composed in particular of free-radically polymerizedunits of

-   20 to 34%, preferably 25 to 33%, more preferably 28 to 32% by weight    methacrylic acid or acid; methacrylic acid is preferred;-   20 to 69%, preferably 35 to 65%, more preferably 35 to 55% by weight    methyl acrylate and, if desired,-   0 to 40%, preferably 5 to 35%, more preferably 15 to 35% by weight    ethyl acrylate, with the proviso that the glass transition    temperature of the copolymer (measured without addition of    plasticizer and with a residual monomer content (REMO) of less than    100 ppm, heating rate 10° C./min, nitrogen atmosphere) in accordance    with ISO 11357-2, section 3.3.3 (T_(mg)), is not more than 60° C.,    preferably 40 to 60° C., more preferably 45 to 55° C.

The copolymer is composed preferably essentially to exclusively of themonomers methacrylic acid, methyl acrylate and ethyl acrylate in theproportions indicated above.

Additionally, however, it is possible, without leading to anydeterioration in the essential properties, for small amounts, in therange from 0 to 10%, e.g., from 1 to 5% by weight, of furthervinylically copolymerizable monomers to be present, such as methylmethacrylate, butyl methacrylate, butyl acrylate or hydroxyethylmethacrylate, for example.

Preparation of the Copolymer

The copolymer can be prepared in conventional manner by free-radicaladdition polymerization of the monomers (see, e.g., EP 0 704 207 A2 andEP 0 704 208 A2). The copolymer of the invention is preparable in aconventional manner by free-radical emulsion polymerization in aqueousphase in the presence of preferably anionic emulsifiers, by the processdescribed in DE-C 2 135 073, for example.

The copolymer can be prepared by customary methods of free-radicalpolymerization continuously or batchwise in the presence of free-radicalinitiators and, if desired, regulators for adjusting the molecularweight, in bulk, in solution, by bead polymerization or in emulsion. Theaverage molecular weight Mw (weight average, determined for example bymeasuring the solution viscosity) can be, for example, in the range from80 000 to 1 000 000 (g/mol). Preference is given to emulsionpolymerization in aqueous phase in the presence of water-solubleinitiators and (preferably anionic) emulsifiers.

In the case of bulk polymerization the copolymer can be obtained insolid form by crushing, extrusion, granulation or hot chopping.

Organic Solution

The copolymer can be provided in the form of an organic solution, in aconcentration of from 10 to 30% by weight, for example. Solvents whichcan be used include, for example, acetone, isopropanol or ethanol ormixtures thereof, which may where appropriate include water fractions ofup to about 10% by weight. Preference is given, however, to aqueousdispersions.

Dispersions

The emulsion polymer is preferably produced and employed in the form ofan aqueous dispersion with a concentration of from 10 to 50 percent byweight, in particular from 20 to 40 percent by weight. A preferredcommercial form is a solids content of 30% by weight. For processing,partial neutralization of the methacrylic acid units is not vital; it ispossible, however, in an extent of up to 5 or 0 mol %, for example, ifstabilization or thickening of the coating agent dispersion should bedesired. The weight average value of the latex particle size isgenerally from 40 to 100 nm, preferably from 50 to 70 nm, which ensuresa favorable processing viscosity of less than 1000 mPa·s.

At a relatively high degree of neutralization of from 10 to 50 mol %,for example, or in the case of full neutralization it is possible toconvert the copolymer into a dissolved state.

In order to prepare a solution of the anionic copolymer it is generallynecessary for the acid groups to be partly or fully neutralized. Theanionic copolymer can be stirred into water, for example, gradually in afinal concentration of from 1 to 40% by weight, in the course of whichit can be partly or fully neutralized by addition of a basic substancesuch as NaOH, KOH or ammonium hydroxide, for example, or organic basessuch as triethanolamine, for example. It is also possible to use apowder of the copolymer to which a base—NaOH, for example—has alreadybeen added in the course of its preparation for the purpose of (partial)neutralization, so that the powder is an already (partially) neutralizedpolymer. The pH of the solution is generally above 4, in the range from4 to about 7 for example.

The dispersion can, for example, also be spray-dried or freeze-dried inconventional manner and provided in the form of a redispersible powder(see e.g. EP-A 0 262 326). Alternative methods are those of freezedrying or coagulation and removal of the water by squeezing in anextruder with subsequent granulation (see e.g. EP-A 0 683 028).

Surprisingly it has been found that copolymer dispersions formed fromspray-dried or freeze-dried and redispersed powders exhibit an increasedshear stability. This is an advantage particularly in the context ofspray application. This advantage is manifested to a particularly highextent when the copolymer present in the dispersion is from 2 to 10 mol% in partially neutralized form (based on the acid groups present in thecopolymer). Preference is given for this purpose to partialneutralization by adding NaOH. There is preferably an anionic emulsifierpresent in an amount of from 0.1 to 2% by weight. Particular preferenceis given to sodium lauryl sulfate as emulsifier.

Ready to Use

The copolymer can be present in powder form in a mixture with customarypharmaceutical excipients in a readily redispersible form. If thestarting product is a copolymer powder, an already partially neutralizedpowder, for example, then this powder can be ground and/or mixed and/orformulated dry with customary pharmaceutical excipients, such as talc,soluble dyes, dye pigments or stabilizers, for example. The formulationis referred to as a ready to use formulation, which following additionof water and a comparatively short redispersing time can be useddirectly as a ready-made or at least substantially complete coatingagent or binder.

Mechanical Properties

In the area of the copolymer composition selected in accordance with theinvention a sudden increase in mechanical stability is found. Themechanical stability of the copolymer, even without plasticizer, isdistinctly improved as compared with noninventive copolymers of similarcomposition but with a higher glass transition temperature. Noninventivecopolymers of similar composition and with glass transition temperaturesbelow 60° C., moreover, no longer have the desired release profile.

The differences are manifested to a particular extent when plasticizeris added. From a level of 1% by weight of plasticizer upward,differences in the breaking elongation behavior (in accordance with DIN53 455) are already measurable. The copolymer can contain 0 to 40% byweight plasticizer. Generally 6 to 30%, preferably 15 to 25% by weightplasticizer is favorable. The plasticizer-containing copolymer can havebreaking elongation values of at least 250%, at least 300%, at least400%, at least 500%, at least 600%.

Polymer Mixtures

In order to control the release of active ingredient it may in certaincases be advantageous to mix other polymers into the copolymer. Thefraction of other polymers in the mixture can vary within wide rangesand lies between 1 and 99%, preferably 10 and 90% by weight, morepreferably between 25 and 85% by weight, based on the polymer mixture.

Examples of such other polymers are: polyvinylpyrrolidones, polyvinylalcohols, anionic (meth)acrylate copolymers of methyl methacrylateand/or ethyl acrylate and methacrylic acid (EUDRAGIT® L 100, EUDRAGIT® S100, EUDRAGIT® L 100-55). Anionic (meth)acrylate copolymers of methylmethacrylate, methyl acrylate and methacrylic acid of the prior art(see, for example, EP-A-0 704 207 or EP-A-0 704 208),carboxymethylcellulose salts, hydroxypropylcellulose (HPMC), neutral(meth)acrylate copolymers of methyl methacrylate and ethyl acrylate (drysubstance from EUDRAGIT® NE 30 D), copolymers of methyl methacrylate andbutyl methacrylate (PLASTOID® B) or (meth)acrylate copolymers containingquaternary ammonium groups (EUDRAGIT® RL or EUDRAGIT® RS).

Multilayer Drug Forms

In order to control the release of active ingredient it may beadvantageous in certain cases to provide the drug form with furtherpolymer or copolymer layers which may be arranged within or outside alayer containing the copolymer of the invention. It is possible, forexample, to add an outer release delay layer or a further outer entericand/or tasteinsulating layer. A further example of this would be theapplication of an outer colored polymer layer, composed for example ofhydroxypropylmethylcellulose (HPMC) and dyes.

Examples of such further polymers are: polyvinylpyrrolidones, polyvinylalcohols, anionic (meth)acrylate copolymers of methyl methacrylateand/or ethyl acrylate and methacrylic acid (EUDRAGIT® L 100, EUDRAGIT® S100, EUDRAGIT® L 100-55). Anionic (meth)acrylate copolymers of methylmethacrylate, methyl acrylate and methacrylic acid of the prior art(see, for example, EP-A-0 704 207 or EP-A-0 704 208),carboxymethylcellulose salts, hydroxypropylmethylcellulose (HPMC),neutral (meth)acrylate copolymers of methyl methacrylate and ethylacrylate (dry substance from EUDRAGIT® NE 30 D), copolymers of methylmethacrylate and butyl methacrylate (PLASTOID® B) or (meth)acrylatecopolymers containing quaternary ammonium groups (EUDRAGIT® RL orEUDRAGIT® RS).

Drug Form

The drug form of the invention is in the form of a tablet, drug formcomprising pellets and/or in the form of an active ingredient matrix,the tablets, pellets and/or active ingredient matrix comprising anactive pharmaceutical substance and a copolymer as coating agent and/orbinder, and, if desired, a core and pharmaceutically customaryexcipients. Tablets normally comprise cores coated with a copolymer;pellets are generally composed of coated cores or else of coatedcrystals of active ingredient. In an active ingredient matrix thecopolymer acts as a binder for the active ingredient.

The term “drug form in the form of a tablet, drug form comprisingpellets and/or in the form of an active ingredient matrix” is intendedto comprehend all common types of drug forms of which the skilled workeris aware. The forms in question include, in particular, tablets,including tablets with retarded or accelerated disintegration, pellets,to be understood to include granules, microparticles or microtablets,tablets compressed to form pellets (multiparticulate drug form), andpellets as a filling in capsules. Transdermal therapy systems in theform, for example, of a patch or a coating are examples of activeingredient matrices. The forms may also be capsules, parts of capsulesor other drug forms, sachets, dry juices, suppositories, pessaries orimplants.

In accordance with the process of the invention the copolymer, incombination if desired with pharmaceutically customary adjuvants, e.g.,plasticizers, mold release agents and/or dyes, can also first beprocessed to form shaped bodies and then an active pharmaceuticalingredient, with or without a core, can be enclosed therein. Thisprocessing may take place preferably by dipping, injection molding orextrusion. The shaped body may be a capsule, the part of a capsule or aweldable film.

Production of the Drug Form

The drug form is prepared by processing the copolymer, the activepharmaceutical ingredient, the core if present and/or thepharmaceutically customary excipients in conventional manner, with orwithout the addition of water, by melting, injection molding, extrusion,wet granulation, casting, spreading, spraying or compression to formtablets or drug forms comprising pellets and/or to form an activeingredient matrix.

Further Uses

As well as being used for drug forms, the copolymer of the invention canalso be used as a constituent or ingredient of cosmetics or nutritionalsupplements. Within the field of cosmetics the copolymer can beincorporated preferably in dissolved form into ointments and creams, forexample, or as a constituent of cosmetic patches. In the case of thenutritional supplements the copolymer can be used, for example, fortaste insulation, as a covering for protecting vitamins or minerals, andfor insulating incompatible constituents.

Active Ingredients

The active ingredients used for the purposes of the invention areintended to be used on or in the human or animal body in order

-   1. to heal, alleviate, prevent or diagnose diseases, ailments,    physical damage or pathological symptoms.-   2. to allow the state, condition or functions of the body, or mental    states, to be identified.-   3. to replace active substances or body fluids produced by the human    or animal body.-   4. to defend against, eliminate or render innocuous pathogens,    parasites or exogenous substances, or-   5. to influence the state, condition or functions of the body, or    mental states.

Drugs in common use can be found in reference works, such as the RoteListe or the Merck Index, for example. In accordance with the inventionit is possible to use any active ingredients which fulfill the desiredtherapeutic activity in the sense of the above definition and whichpossess a sufficient thermal stability.

The formulation of the invention is suitable for administering inprinciple any active pharmaceutical ingredients which are to be releasedpreferentially in the intestine and/or colon, and particularly thosewhich may be administered advantageously in delayed-release form.

Particular mention should be made of active ingredient from thefollowing class of active ingredients: laxatives, analgesics,antibiotics, antirheumatics, antiallergics, antiarrhythmics,antibiotics, antiepileptics, beta-receptor blockers, calcium channelblockers, chemotherapeutics, enzymes, extracts, inhibitors of therennin-angiotensin system, broncholytics/antasthmatics cholinergics,diuretics, circulation promoters, gout agents influenza agents, coronaryagents, osteoporosis agents (biphosphonates), lipid reducers,gastrointestinal agents, peptides, proteins, proton pump blockers,psychopharmaceuticals, platelet aggregation inhibitors urological agentsvenous therapeutic agents, vitamins and minerals.

The drug form of the invention may comprise, for example, the followingactive ingredients: characterized in that as active ingredientparoxetine, reboxetine morphine and its derivatives, tramadol,bisacodyl, sodium fluoride acamprosate Ca, digitoxin, dimethicone, colibacteria, liponic acid, methenamine, budenoside, acetylsalicylic acid,diclofenac, flurbiprophen, indometacin, lonazolac, hydrocortisone,ibuprofen, ketoprofen, prednisolone, propyphenazone, naproxen,paracetamol, flurbiprofen, dimetindene, quinidine, metoprolol,propranolol, oxprenolol, pindolol, atenolol, metoprolol, disopyramide,verapamil, diltiazem, gallopamil, nifedipine, nicardipine, nisoldipine,nimodipine, amlodipine, theophylline, salbutamol, terbutaline, ambroxol,aminophylline, carbamazepine, alendronate, etidronate, clodronate,pamidronate, ibandronate choline theophyllinate, pyridostigmine,piretanide, furosemide, pentoxyifylline, naftidrofuryl, buflomedil,xantinol nicotinate, bencyclane, allopurinol, norephedrine,clorphenamine isosorbide mononitrate, isosorbide dinitrate, glyceroltrinitrate, molsidomine, bezafibrate, fenofibrate, gemfibrozil,cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin,simvastatin, 5-aminosalicylic acid, sulfasalazine, budenoside,natamycin, preglumetacin sulfasalacine, nitrofurantion xantinol,metoclopramid, amitriptyline, dibenzepine, venlafaxin, thioridazine,oxazepam, omeprazole, lanzoprazole, pantoprazole, rabeprazole,perprazole, esomprazole, nitrofurantoin, rutoside, garlic, aescin,bromelaine, pancreatin or trypsin, an insulin, a human growth hormone(hGH), corbaplatin, intron A, calcitonin, cromalyn, an interferon, acalcitonin, granulocyte colony stimulating factor (G-CSF), aninterleukin, a kinine, parathyroid hormones, glucagon, pindolol,prosomatostatin, a somatostatin, detirelix, cetrorelix, vasopressin,1-deaminocysteine-8-D-arginine vasopressin, leuprolide acetate or anantigen obtained from grasses or other plants, such as rye, wheat,barley, oats, Bermuda grass, horsetail, maple, elm, oak, plane, poplar,cedar, horsetail, thistles, IgG, specific vaccines or monoclonalantibodies, dry plant extract, ascorbic acid, aspartamic acid, valproicacid zinc, and potassium, sodium, lithium and their salts usedpharmaceutically.

The active ingredients can if desired also be used in the form of theirpharmaceutically acceptable salts or derivatives, and in the case ofchiral active ingredients not only optically active isomers but alsoracemates or diastereoisomer mixtures can be used. If desired thecompositions of the invention may also comprise two or more activepharmaceutical ingredients.

Pharmaceutically Customary Excipients

a) Plasticizers

Substances suitable as plasticizers generally have a molecular weight ofbetween 100 and 20 000 and contain one or more hydrophilic groups intheir molecule, e.g., hydroxyl, ester or amino groups. Suitability ispossessed by citrates, phthalates, sebacates and castor oil. Examples ofsuitable plasticizers are alkyl citrates, glycerol esters, alkylphthalates, alkyl sebacates, sucrose esters, sorbitan esters andpolyethylene glycols 4000 to 20 000. Preferred plasticizers are tributylcitrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate anddiethyl sebacate. It is preferred to add 6 to 30%, especially 15 to 25%by weight of a plasticizer to the copolymer, based on the dry weight ofthe copolymer.

b) Further Pharmaceutically Customary Excipients

Mention may be made here of, for example, stabilizers, dyes,antioxidants, wetting agents, pigments, gloss agents, etc. They serveprimarily as processing assistants and are intended to ensure thepossibility of a reliable and reproducible production process and goodlong-term storage stability. Pharmaceutically customary excipients canbe present in amounts from 0.001% by weight to 300% by weight,preferably 0.1 to 100% by weight, based on the copolymer.

Examples of dry standardizers are: alumina, magnesium oxide, kaolin,talc, silica (Aerosils), barium sulfate, carbon black and cellulose.

Unlike dry standardizers, mold release agents have the property ofreducing the force of adhesion between the moldings and the surface ofthe mold in which the molding is produced. This makes it possible toproduce moldings which are not crushed and have not undergonegeometrical deformation. Mold release agents are generally partlycompatible or incompatible with the polymers in which they areparticularly effective. As a result of the partial compatibility orincompatibility, the injection of the melt into the mold cavity isaccompanied by migration into the interface of the transition betweenmold wall and molding. In order that mold release agents can migratewith particular advantage, the melting point of the mold release agentmust be 20° C. to 100° C. below the processing temperature of thepolymer.

Examples of (mold) release agents are: esters of fatty acids or fattyacid amides, aliphatic long-chain carboxylic acids, fatty alcohols andtheir esters, montan waxes or paraffin waxes and metal soaps, of whichmention may be made in particular of glycerol monostearate, stearylalcohol, glycerol behenates, cetyl alcohol, palmitic acid, carnauba wax,beeswax, etc.

Production of Multiparticulate Drug Forms

The invention is particularly suitable for producing multiparticulatedrug forms, since the copolymer of the invention withstands the highpressures accompanying the compression of the pellets with the filler.

The production of multiparticulate g forms by compression of apharmaceutically customary binder with active ingredient particles isdescribed in detail in, for example, Beckert et al. (1996), “Compressionof enteric-coated pellets to disintegrating tablets”, InternationalJournal of Pharmaceutics 143, pp. 13-23, and in WO 96/01624.

Active ingredient pellets can be produced by applying an activeingredient by means of a layering operation. For that purpose activeingredient is homogenized together with further excipients (releaseagents, plasticizers if appropriate) and dissolved or suspended in abinder. The liquid can be applied to placebo pellets or other suitablecarrier materials by means of a fluid-bed process, the solvent orsuspension medium being evaporated (reference: International Journal ofPharmaceutics 143, pp. 13-23). The production process may be followed bya drying step. The active ingredient can be applied in a number oflayers.

Some active ingredients, acetylsalicylic acid being one example, arecommercially customary in the form of active ingredient crystals and canbe used in that form instead of active ingredient pellets.

Film coatings on active ingredient pellets are normally applied influid-bed devices. Formula examples are mentioned in this specification.Film formers are normally mixed with plasticizer and release agent by asuitable method. The film formers may be present in this context as asolution or suspension. The film-forming auxiliaries may likewise be insolution or suspension. Organic or aqueous solvents or dispersion mediamay be used. In order to stabilize the dispersion it is possibleadditionally to use stabilizers (example: Tween 80 or other suitableemulsifiers and/or stabilizers).

Examples of release agents are glycerol monostearate or other suitablefatty acid derivatives, silica derivatives or talc. Examples ofplasticizers are propylene glycol, phthalates, polyethylene glycols,sebacates or citrates, and other substances mentioned in the literature.

Applied between the active ingredient layer and gutsoluble copolymerlayer there may be a separating layer which serves to separate activeingredient and coating material for the purpose of preventinginteractions. This layer may be composed of inert film formers (e.g.,HPMC, HPC or (meth)acrylic acid copolymers) or, for example, talc orother suitable pharmaceutical substances. It is also possible to usecombinations of film formers and talc or similar substances.

It is also possible to apply a separating layer composed of partly orfully neutralized copolymer dispersions.

Mixtures for producing tablets from coated particles are prepared bymixing the pellets with suitable binders for tableting, if necessaryadding disintegration promoters, and if necessary adding lubricants.Mixing can take place in suitable machines. Unsuitable mixers are thosewhich lead to damage to the coated particles, plowshare mixers being anexample. In order to obtain suitable short disintegration times aspecific sequence may be necessary in the addition of the auxiliaries tothe coated particles. By premixing magnesium stearate as lubricant ormold release agent with the coated particle it is possible tohydrophobicize the surface of said particle and so to prevent sticking.

Mixtures suitable for tableting normally contain 3 to 15% by weight of adisintegration assistant, e.g., Kollidon CL and, for example, 0.1 to 1%by weight of a lubricant and mold release agent such as magnesiumstearate. The binder fraction is determined in accordance with therequired fraction of coated particles.

Examples of typical binders include Cellactose®, microcrystallinecellulose, calcium phosphates, Ludipress®, lactose or other suitablesugars, calcium sulfates or starch derivatives. Preference is given tosubstances having a low bulk density.

Typical disintegration assistants (disintegrants) are crosslinked starchderivatives or cellulose derivatives, and also crosslinkedpolyvinylpyrrolidone. Cellulose derivatives are also suitable. Throughthe selection of an appropriate binder it may be possible to do withoutthe use of disintegration assistants.

Typical lubricants and mold release agents are magnesium stearates orother suitable salts of fatty acids or substances listed in theliterature for this purpose (e.g. lauric acid, calcium stearate, talc,etc). Where suitable machines (e.g., tableting press with externallubrication) or suitable formulations are used it may be unnecessary touse a lubricant and mold release agent in the mixture.

An auxiliary to improve flow may be added to the mixture if desired(e.g., highly disperse silica derivatives, talc, etc).

Tableting can take place on customary tableting presses, eccentric orrotational tableting presses, under compression forces in the range from5 to 40 kN, preferably 10-20 kN. The tableting presses may be equippedwith systems for external lubrication. Where appropriate, specialsystems are employed for die charging which avoid die charging by meansof stirring paddles.

Further production processes for the drug form of the invention.

Application process takes place by means of spray application fromorganic solution, or preferably aqueous dispersions by melting or bydirect powder application. The critical factor for the version is thatuniform, pore-free coatings are formed.

Application processes in accordance with the state of the art see forexample Bauer, Lehmann, Osterwald, Rothgang, “Uberzogene Arzneiformen”Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, chap. 7, pp.165-196.

For the application, relevant properties, required tests andspecifications are listed in pharmacopeias.

Details can be found in common textbooks, e.g.:

-   Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie; Verlag    Chemie Weinheim—Beerfield Beach/Florida—Basel.-   Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische Technologie,    Georg Thieme Verlag Stuttgart (1991), especially chapters 15 and 16,    pp. 626-642.-   Gennaro, A. R., (Editor), Remington's Pharmaceutical Sciences, Mack    Publishing Co., Easton Pa. (1985), chapter 88, pp. 1567-1573.-   List, P. H. (1982): Arzneiformeniehre, Wissenschaftliche    Verlagsgesellschaft mbH, Stuttgart.    Advantageous Effects of the Invention

A rapid release of active ingredient with simultaneous insulation of theactive ingredient, taste protection and/or odor protection can beachieved, for example, in thinly covered drug forms or cosmetics ornutritional supplements. In this case the coat thicknesses are, forexample, in the range from 1 to 15 μm.

A slightly delayed release of active substance in stomach and intestinecan be achieved, for example, in covered drug forms or cosmetics ornutritional supplements. In this case the coat thicknesses are, forexample, in the range from 15 to 40 μm.

Gastric juice resistance and, where appropriate, an increase inbioavailability can be achieved, for example, in covered drug forms orcosmetics or nutritional supplements. In this case the coat thicknessesare, for example, in the range from 40 to 60 μm.

Active ingredient release in deeper sections of the intestine and, whereappropriate, an increase in bioavailability can be achieved, forexample, in covered drug forms or cosmetics or nutritional supplements.In this case the coat thicknesses are, for example, in the range from 70to 100 μm.

Accelerated release in conjunction with an increase in bioavailabilitycan be achieved from matrix systems in which the copolymer fraction in %by weight is greater than the active ingredient fraction.

EXAMPLES

Preparation of the Copolymers:

1. Preparation of the Dispersions

A reaction vessel is charged with 31.8 kg of water and 44 g of sodiumlauryl sulfate and this initial charge is heated to 75° C. In parallel,in a stirred preparation vessel, 24 kg of water, 40 g of sodium laurylsulfate 280 g of Polysorbat 80, 40 g of initiator (e.g., sodiumpersulfate), 62.4 g of regulator (e.g., 2-ethylhexyl thioglycolate) and24 kg of monomers in accordance with the proportions indicated below, in% by weight, are emulsified. To start the reaction a further 16 g ofinitiator (e.g., sodium persulfate) in solution in 600 ml of water areadded to the reactor vessel and the preemulsion is metered in at 75° C.over the course of 4 h. After the end of the addition the resultantdispersion is stirred at 75° C. for 2 more, then cooled and filtered.

The breaking elongation of the copolymers was determined on sample filmsin accordance with DIN 53 455.

The glass transition temperature T_(mg) in [° C.] was determined onsample specimens in accordance with ISO 11357-2 (the measurement wasconducted with a heating rate (thermal cycle rate, 9.2.4) of 10° C./min;in order to avoid relaxation effects the second heating operation wasemployed for the determination; measurement under nitrogen atmosphere).

Examples 1 to 5 Examples 1 and 2 (Comparative Examples), Examples 3 to 5(Inventive)

The copolymer compositions and measurement values values found aresummarized the table below. Examples 1 2 3 4 5 Methyl acrylate 40 70 4050 60 Ethyl acrylate 25 — 30 20 10 Methacrylic acid 35 30 30 30 30Triethyl citrate [%] 20 20 20 20 20 T_(mg) [° C.] 64 59 54 51 52Breaking elongation 207 95 635 586 377 [%]Results:

The copolymer of example 1 has too high a fraction of methacrylic acid(35% by weight), which results in an excessive glass transitiontemperature of 64° C. The breaking elongation is much lower than in thecase of the inventive examples 3 to 5. Although the copolymer of example2 is in the claimed T_(mg) range, the breaking elongation is lower thanin comparative example 1, apparently as a result of an excessive methylacrylate fraction (70% by weight), and much lower than in the inventiveexamples 3 to 5.

Examples 6 and 7

The breaking elongation values of films of the copolymers of example 1(comparative example) and example 3 (inventive) were measured with andwithout various amounts of added plasticizer. Example 6 7 Copolymer [%by weight] Methyl acrylate/ 40 40 Ethyl acrylate 25 30 Methacrylic acid35 30 T_(mg) [° C.] without 64 54 plasticizer Added triethyl citrate [%by weight] Breaking elongation [%]  0*  0*  0* 1 0 2 2 0 1 3 0 3 5 0 31 6 0 115  8 0 139  10  0 268  20  359  639 *= the breaking elongation value 0 [%] reproduces a very low breakingelongation which could no longer be precisely determined. In a hand testit is noticed that the copolymer film of example 7 is mechanically moreresistant even without plasticizer than the comparable copolymer film ofexample 6.

Example 8

An emulsion polymer with a solids content of 30%, in accordance withexample 3, is admixed with 1 N sodium hydroxide solution, with gentlestirring, so that 4% of the carboxyl groups present are neutralized.This gives a milky liquid of low viscosity which after drying at roomtemperature forms clear films which dissolve in artificial intestinaljuice at a pH of 6.8.

Example 9

An emulsion polymer with a solids content of 30%, in accordance withexample 3, is admixed with 1 N sodium hydroxide solution, with gentlestirring, so that 8% of the carboxyl groups present are neutralized.This gives a milky liquid of low viscosity which after drying at roomtemperature forms clear films which dissolve in artificial intestinaljuice at a pH of 6.8.

Example 10

An emulsion polymer with a solids content of 30%, in accordance withexample 3, is admixed with 1 N sodium hydroxide solution, with gentlestirring, so that 20% of the carboxyl groups present are neutralized.This gives a clouded liquid of high viscosity which indicatesdissolution of the polymer beginning already. After drying at roomtemperature it forms clear films.

Example 11

In an emulsion polymer with a solids content of 30%, in accordance withexample 3, 0.85% of sodium lauryl sulfate (calculated based on polymer)is dissolved at room temperature with gentle stirring. This gives amilky liquid of low viscosity which after drying at room temperatureforms films which dissolve in artificial intestinal juice at a pH of6.8.

Example 12

An emulsion polymer with a solids content of 30%, in accordance withexample 3, is admixed with 1 N sodium hydroxide solution, with gentlestirring, so that 5% of the carboxyl groups present are neutralized.Additionally 0.5% of sodium lauryl sulfate (calculated based on polymer)is dissolved at room temperature with gentle stirring. This gives amilky liquid of low viscosity which after drying at room temperatureforms films which dissolve in artificial intestinal juice at a pH of6.8.

Example 13

A modified emulsion polymer in accordance with example 12 is frozen in aflask at about −78° C. and then freeze dried at room temperature. Thisgives a fine white powder having a bulk density of 208 g/l. The valuemay be significantly higher if the process conditions are changed toresemble those encountered in production.

Example 14

A modified emulsion polymer, in accordance with example 12, is spraydried in a spray tower using a disk (rotational speed 25 000/min). Thedispersion was supplied by means of a hose pump. The entry temperatureof the drying air was 100° C., the temperature of the outgoing air 50°C. This gives a fine white powder having a bulk density of 358 g/l.

Example 15

20 g of the freeze-dried powder from example 13 are introduced into 80 gof cleaned water at room temperature, with gentle stirring, and stirringis maintained for 2 hours. This gives a milky liquid of low viscositywhich after drying at room temperature forms clear films which dissolvein artificial intestinal juice at a pH of 6.8. In a stress test carriedout by pumping the dispersion in circulation using a hose pump (with aninternal diameter of 2 mm) for 24 hours, this dispersion provedparticularly stable to shearing.

Example 16

20 g of the freeze-dried powder from example 14 are introduced into 80 gof cleaned water at room temperature, with gentle stirring, and stirringis maintained for 2 hours. This gives a milky liquid of low viscositywhich after drying at room temperature forms clear films which dissolvein artificial intestinal juice at a pH of 6.8. In a stress test carriedout by pumping the dispersion in circulation using a hose pump (with aninternal diameter of 2 mm) for 24 hours, this dispersion provedparticularly stable to shearing.

Example 17 Determination of Dissolution Rate

In a coating pan, glass beads are coated with an emulsion polymer inaccordance with example 3 by spray application with simultaneous dryingwith hot air. Subsequently the dissolution rate of the polymer isdetermined at different pH levels in an autotitrator at 37° C. bytitrating with sodium hydroxide solution. The following approximatedfigures are obtained: Intrinsic dissolution rate pH [mg/g * min] 5.0 25.5 8 5.8 8 6.0 28 6.2 99 6.5 182 6.8 246

Example 18 Coating on Crystals

Emulsion polymer from example 3 460 g Glycerol monostearate (GMS) 7 gPolysorbat 80 (33% aqueous solution) 9 g Water, purified 264 gare used to prepare a spray suspension, by emulsifying GMS andPolysorbat 80 at 65° C. in the water and incorporating this emulsioninto the emulsion polymer with stirring.

In a 35 cm coating pan AR 400 (from ERWEKA, Heusenstamm), using a Bingospray gun (from Walther), 2.5 kg of placebo tablets (diameter 10 mm,weight 303 mg, fracture resistance 11 N) are coated under the followingconditions: Nozzle diameter 1.2 mm Rotational speed 40/min Feed airtemperature 50-60° C. Product temperature 28-32° C. Spraying pressure1.0 bar Spraying rate about 2.5 g/min After drying 16 h, roomtemperature on racks

The polymer add-on was. 6 mg polymer/cm².

The coated tablets showed no disintegration after 120 minutes in thePharm. Eur. disintegration test. In pH 6.8 buffer solution, however, allof the tablets had disintegrated after 5-8 min.

Example 19 Coating on Crystals

Emulsion polymer from example 3 500 g Glycerol monostearate (GMS) 8 gPolysorbat 80 (33% aqueous solution) 9 g Water, purified 288 gare used to prepare a spray suspension, by emulsifying GMS andPolysorbat 80 at 65° C. in the water and incorporating this emulsioninto the emulsion polymer with stirring.

1 kg of acetylsalicylic acid crystals are coated in a fluidized-bedapparatus GPCG 1 with top spray insert (from GLATT, Binzen) under thefollowing conditions: Nozzle diameter 1.2 mm Feed air temperature 40-50°C. Feed air quantity 66-70 m³/h Product temperature 28-30° C. Sprayingpressure 1.0 bar Spraying rate about 7 g/min After drying 2 h, 40° C. onracks

The polymer add-on was 15%.

The coated crystals showed the following figures in the Pharm. Eur.dissolution test: Time Release [min] pH [%] 15 1.2 0.3 30 1.2 0.9 60 1.22.5 90 1.2 4.2 120 1.2 5.9 130 6.8 35.9 140 6.8 65.1 150 6.8 83.2 1606.8 92.4 170 6.8 96.6 180 6.8 98.1

Example 20 Coating on Tablets

Emulsion polymer from example 14 141 g Glycerol monostearate (GMS) 7 gPolysorbat 80 (33% aqueous solution) 9 g Water, purified 598 gare used to prepare a spray suspension, by emulsifying GMS andPolysorbat 80 in the water at 65° C. and cooling the emulsion to roomtemperature. The polymer powder is introduced into this preemulsion anddispersed by simple stirring for 2 hours.

In a coating pan (diameter 35 cm) with AR 400 drive (from Erweka,Heuselstamm) a mixture of 2300 g of placebo cores (10 mm diameter, 300mg weight) and 200 g of quinidine sulfate tablets (5% active ingredientcontent, 10 mm diameter, 300 mg weight) is coated under the followingconditions: Nozzle diameter 1.2 mm Rotational speed of pan 40/min Feedair temperature 40-55° C. Product temperature 28-30° C. Sprayingpressure 1.0 bar Spraying rate about 2.9 g/min After drying 2 h, 40° C.on racks

The polymer add-on was 6%.

The coated quinidine sulfate tablets showed the following figures in thePharm. Eur. dissolution test: Time Release [min] pH [%] 10 1.2 <1.0 601.2 <1.0 120 1.2 <1.0 140 6.8 93.1 160 6.8 98.7 180 6.8 99.5

Example 21 Coating on Tablets

Emulsion polymer from example 14 141 g Glycerol monostearate (GMS)  4 gPolysorbat 80 (33% aqueous solution)  5 g Quinoline yellow  35 gTitanium dioxide  35 g Water, purified 865 gare used to prepare a spray suspension as follows: GMS is emulsified at65° C. in 577 g of water and Polysorbat 80 and the emulsion is cooled toroom temperature with stirring. The polymer powder is introduced intothis preemulsion and dispersed by simple stirring for 2 hours. Thepigments, quinoline yellow and titanium dioxide, are dispersed in 288 gof water using a homogenizer (Ultra Turrax) for 5 minutes. Thissuspension is introduced into the polymer dispersion with gentlestirring.

In a coating pan (diameter 35 cm) with AR 400 drive (from Erweka,Heuselstamm) a mixture of 2300 g of placebo cores (10 mm diameter, 300mg weight) and 200 g of quinidine sulfate tablets (5% active ingredientcontent, 10 mm diameter, 300 mg weight) is coated under the followingconditions: Nozzle diameter 1.2 mm Rotational speed of pan 40/min Feedair temperature 40-55° C. Product temperature 28-30° C. Sprayingpressure 1.0 bar Spraying rate about 2.9 g/min After drying 2 h, 40° C.on racks

The polymer add-on was 6%.

The coated quinidine sulfate tablets showed the following figures in thePharm. Eur. dissolution test: Time Release [min] pH [%] 10 1.2 <1.0 601.2 <1.0 120 1.2 <1.0 140 6.8 47.2 160 6.8 95.2 180 6.8 99.2

1. A process for producing a drug form as a tablet, as a drug formcomprising pellets and/or in the form of an active ingredient matrix,the tablets, pellets and/or active ingredient matrix comprising anactive pharmaceutical ingredient and a copolymer as coating agent and/orbinder, and, optionally, a core and pharmaceutically customaryexcipients, by processing the copolymer, the active pharmaceuticalingredient, the core if present and/or the pharmaceutically customaryexcipients in a conventional manner by melting, injection molding,extrusion, wet granulation, casting, dipping, spreading, spraying orcompression to form tablets, a drug form comprising pellets and/or anactive ingredient matrix, wherein a copolymer is used which comprises 20to 34% by weight methacrylic acid and/or acrylic acid, 20 to 69% byweight methyl acrylate and  0 to 40% by weight ethyl acrylate and/or,

 optionally, 0 to 10% by weight further vinylically copolymerizablemonomers, wherein the glass transition temperature of the copolymer inaccordance with ISO 11357-2, section 3.3.3, is not more than 60° C. 2.The process as claimed in claim 1, wherein 6 to 30% by weight of aplasticizer are added to the coating agent and binder.
 3. The process asclaimed in claim 1, wherein the copolymer is used in the form of adispersion for producing the drug form.
 4. The process as claimed inclaim 3, wherein the dispersion has been obtained by redispersing afreeze-dried or spray-dried copolymer powder.
 5. The process as claimedin claim 3, wherein from 2 to 10% by weight of the copolymer present inthe dispersion is in partly neutralized form.
 6. The process as claimedin claim 5, wherein the partial neutralization has been brought about byadding NaOH.
 7. The process as claimed in claim 3, wherein an anionicemulsifier is present in an amount of from 0.1 to 2% by weight.
 8. Theprocess as claimed in claim 7, wherein sodium lauryl sulfate is presentas emulsifier.
 9. The process as claimed in claim 1, wherein thecopolymer, optionally in combination with pharmaceutically customaryadditives, is processed to form shaped bodies and an activepharmaceutical ingredient is enclosed therein.
 10. The process asclaimed in claim 8, wherein the shaped body is a capsule, the part of acapsule or a weldable film.
 11. A drug form produced by the process asclaimed in claim
 1. 12. The drug form as claimed in claim 11, whereinthe drug form comprises tablets, tablets with delayed or accelerateddisintegration, pellets, tablets compressed from pellets, pellets as afilling in capsules, a transdermal therapy system in the form of a patchor a swear, capsules, parts of capsules or other drug forms, sachets,dried juices, suppositories, pessaries or implants.
 13. The drug form asclaimed in claim 11, wherein an active ingredient is present from theactive ingredients class of the laxatives, analgesics, antibiotics,antirheumatics, antiallergics, antiarrhythmics, antibiotics,antiepileptics, beta-receptor blockers, calcium channel blockers,chemotherapeutics, enzymes, extracts, inhibitors of therennin-angiotensin system, broncholytics/antasthmatics cholinergics,diuretics, circulation promoters, gout agents influenza agents, coronaryagents, osteoporosis agents (biphosphonates), lipid reducers,gastrointestinal agents, peptides, proteins, proton pump blockers,psychopharmaceuticals, platelet aggregation inhibitors urological agentsvenous therapeutic agents, vitamins and minerals.
 14. The drug form asclaimed in claim 13, wherein the active ingredient is selected from thegroup consisting of paroxetine, reboxetine morphine and its derivatives,tramadol, bisacodyl, sodium fluoride acamprosate Ca, digitoxin,dimethicone, coli bacteria, lipoic acid, methenamine, budenoside,acetylsalicylic acid, diclofenac, flurbiprophen, indometacin, lonazolac,hydrocortisone, ibuprofen, ketoprofen, prednisolone, propyphenazone,naproxen, paracetamol, flurbiprofen, dimetindene, quinidine, metoprolol,propranolol, oxprenolol, pindolol, atenolol, metoprolol, disopyramide,verapamil, diltiazem, gallopamil, nifedipine, nicardipine, nisoldipine,nimodipine, amlodipine, theophylline, salbutamol, terbutaline, ambroxol,aminophylline, carbamazepine, alendronate, etidronate, clodronate,pamidronate, ibandronate, choline theophyllinate, pyridostigmine,piretanide, furosemide, pentoxifylline, naftidrofuryl, buflomedil,xantinol nicotinate, bencyclane, allopurinol, norephedrine,clorphenamine isosorbide mononitrate, isosorbide dinitrate, glyceroltrinitrate, molsidomine, bezafibrate, fenofibrate, gemfibrozil,cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin,simvastatin, 5-aminosalicylic acid, sulfasalazine, budenoside,natamycin, preglumetacin sulfasalacine, nitrofurantion xantinol,metoclopramid, amitriptyline, dibenzepine, venlafaxin, thioridazine,oxazepam, omeprazole, lanzoprazole, pantoprazole, rabeprazole,perprazole, esomprazole, nitrofurantoin, rutoside, garlic, aescin,bromelaine, pancreatin or trypsin, an insulin, a human growth hormone(hGH), corbaplatin, intron A, calcitonin, cromalyn, an interferon, acalcitonin, granulocyte colony stimulating factor (G-CSF), aninterleukin, a kinine, parathyroid hormones, glucagon, pindolol,prosomatostatin, a somatostatin, detirelix, cetrorelix, vasopressin,1-deaminocysteine-8-D-arginine vasopressin, leuprolide acetate or anantigen obtained from grasses or other plants, such as rye, wheat,barley, oats, Bermuda grass, horsetail, maple, elm, oak, plane, poplar,cedar, horsetail, thistles, IgG, specific vaccines or monoclonalantibodies, dry plant extract, ascorbic acid, aspartamic acid, valproicacid zinc, and potassium, sodium, lithium and their salts usedpharmaceutically, and mixtures thereof.
 15. A copolymer suitable forproducing a drug form as claimed in claim
 11. 16. The copolymer asclaimed in claim 15, wherein the copolymer is in the form of a partlyneutralized powder.
 17. The copolymer as claimed in claim 15, whereinthe copolymer is in powder form in a mixture with customarypharmaceutical excipients in a readily redispersible form.
 18. A methodof producing a drug form, which comprises: incorporating the copolymerclaimed in claim 15 into the drug form.
 19. A method of producingcosmetic or a nutritional supplement, which comprises: incorporating thecopolymer claimed in 15 into the cosmetic or the nutritional supplement.